Deficiency of the lipoprotein receptor, scavenger receptor class B type I receptor (SR-BI), might possibly explain, at least in part, some aspects of infertility in humans. SR-BI is a physiologically relevant lipoprotein receptor that mediates the uptake of cholesteryl esters (CE) from the core of lipoproteins (1). SR-BI has also been shown to colocalize in the perinuclear region of cells, with as yet an undefined function (2). It has been shown to be highly expressed in liver and steroidogenic tissues, with particularly high levels found in ovarian tissues (3). SR-BI deficiency is significantly associated with infertility in female mice (4). These female knockout mice have been shown to ovulate dysfunctional oocytes and embryogenesis is abnormal (5). Interestingly, fertility can be restored with either the addition of probucol, a cholesterol lowering antioxidant drug (3) in the chow diet, or by genetically restoring liver SR-BI protein expression (6).
Little is known regarding the role of SR-BI in human fertility. The present inventor with collaborators was the first to show that infertile women with low expression of SR-BI RNA in granulosa cells isolated during oocyte retrievals had significantly lower plasma estradiol levels and lower number of retrieved and fertilized oocytes (7). Other evidence for the role of SR-BI on aspects of ovarian steroidogenesis has been based on the results of ex vivo studies in non-human primates and rat granulosa cells. For instance, Cherian-Shaw reported that SR-BI RNA levels increased steadily by ˜30-fold in macaque granulosa cells 24 h after stimulation by human chorionic gonadotropin (hCG), whereas LDL receptor expression initially increased but then decreased to low basal levels during this early time period (8). Earlier work by Azhar et al. (9) showed that induction of SR-BI expression in rat granulosa cells was significantly associated with increased CE uptake from HDL and with increased total progestin secretion. These investigators subsequently showed that LDL receptor deficiency had minimal effect on murine ovarian progesterone secretion (10).
One goal of the present investigation was to define the effect of SR-BI protein deficiency on progesterone secretion in cultured human granulosa HGL5 cells, with confirmatory findings in primary human granulosa cells isolated during oocyte retrievals. In agreement with other investigators, the present inventor and her collaborators have found that LDL is the preferential lipoprotein supporting steroidogenesis (11,12,13,14). SR-BI, in contrast to the LDL receptor (LDLR), appears to have a major effect on progesterone secretion. Deficiency of SR-BI significantly reduced RNA expression of p450 side-chain cleavage (SCC), 3β-hydroxysteroid dehydrogenase (3βHSD), and steroidogenic acute regulatory protein (StAR).